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Número de publicaciónUS20030027833 A1
Tipo de publicaciónSolicitud
Número de solicitudUS 10/141,496
Fecha de publicación6 Feb 2003
Fecha de presentación7 May 2002
Fecha de prioridad7 May 2001
También publicado comoCA2446060A1, US20050152957, WO2002089849A1, WO2002089849B1
Número de publicación10141496, 141496, US 2003/0027833 A1, US 2003/027833 A1, US 20030027833 A1, US 20030027833A1, US 2003027833 A1, US 2003027833A1, US-A1-20030027833, US-A1-2003027833, US2003/0027833A1, US2003/027833A1, US20030027833 A1, US20030027833A1, US2003027833 A1, US2003027833A1
InventoresGary Cleary, Sri Mudumba, Shohreh Parandoosh, Colin Cleary, Raj Birudaraj, Pathamar Park
Cesionario originalCleary Gary W., Sri Mudumba, Shohreh Parandoosh, Cleary Colin J., Raj Birudaraj, Pathamar Park
Exportar citaBiBTeX, EndNote, RefMan
Enlaces externos: USPTO, Cesión de USPTO, Espacenet
Compositions and delivery systems for administration of a local anesthetic agent
US 20030027833 A1
Resumen
A pharmaceutical composition is provided for topical administration of a local anesthetic agent. The composition comprises (a) a therapeutically effective amount of a local anesthetic agent and (b) a pharmaceutically acceptable, nonliposomal carrier comprised of a monohydric alcohol, a penetration enhancer, and polymer, which may be a hydrophilic polymer, a hydrophobic polymer or a combination thereof. The composition can be in the form of a gel, or it may form a film following application to a patient's body surface and evaporation of the monohydric alcohol. The composition provides rapid onset of local anesthesia as well as penetration of the active agent into the skin. Methods and drug delivery systems for administration of local anesthetic agents are also provided.
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Reclamaciones(56)
We claim:
1. A pharmaceutical composition comprising (a) a therapeutically effective amount of a local anesthetic agent and (b) a pharmaceutically acceptable, nonliposomal carrier comprised of a monohydric alcohol, an effective penetration enhancing amount of a penetration enhancer, and a polymer selected from the group consisting of hydrophilic polymers, hydrophobic polymers and combinations thereof, wherein local anesthetic activity is provided within about thirty minutes of application of the composition to a patient's body surface.
2. The composition of claim 1, wherein the local anesthetic agent is selected from the group consisting of acetamidoeugenol, alfadolone acetate, alfaxalone, amucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, burethamine, butacaine, butaben, butanilicaine, buthalital, butoxycaine, carticaine, 2-chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, diperadon, dyclonine, ecgonidine, ecgonine, ethyl aminobenzoate, ethyl chloride, etidocaine, etoxadrol, β-eucaine, euprocin, fenalcomine, fomocaine, hexobarbital, hexylcaine, hydroxydione, hydroxyprocaine, hydroxytetracaine, isobutylp-aminobenzoate, kentamine, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methohexital, methyl chloride, midazolam, myrtecaine, naepaine, octacaine, orthocaine, oxethazaine, parethoxycaine, phenacaine, phencyclidine, phenol, piperocaine, piridocaine, polidocanol, pramoxine, prilocaine, procaine, propanidid, propanocaine, proparacaine, propipocaine, propofol, propoxycaine, pseudococaine, pyrrocaine, risocaine, salicyl alcohol, tetracaine, thialbarbital, thimylal, thiobutabarbital, thiopental, tolycaine, trimecaine, zolamine, and combinations thereof.
3. The composition of claim 2, wherein the local anesthetic agent is selected from the group consisting of tetracaine, lidocaine, prilocaine, benzocaine, and combinations thereof.
4. The composition of claim 3, wherein the local anesthetic agent is tetracaine.
5. The composition of claim 1, wherein the amount of the local anesthetic agent represents in the range of about 0.1 wt. % to about 50 wt. % of the composition.
6. The composition of claim 5, wherein the amount of the local anesthetic agent represents in the range of about 0.1 wt. % to about 30 wt. % of the composition.
7. The composition of claim 6, wherein the amount of the local anesthetic agent represents in the range of about 0.1 wt. % to about 10 wt. % of the composition.
8. The composition of claim 1, wherein the monohydric alcohol is selected from the group consisting of methanol, ethanol, denatured ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, lauryl alcohol, tridecanol, myristyl alcohol, pentadecanol and palmityl alcohol, isopropyl alcohol, isobutyl alcohol, sec-butyl alcohol, t-butyl alcohol, cyclohexyl alcohol, phenol, benzyl alcohol, and combinations thereof.
9. The composition of claim 1, wherein the amount of the monohydric alcohol represents in the range of about 1 wt. % to about 40 wt. % of the composition.
10. The composition of claim 1, wherein the penetration enhancer is selected from the group consisting of dimethylsulfoxide, decylmethylsulfoxide, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, sodium laurate, sodium lauryl sulfate, cetyltrimethyl-ammonium bromide, benzalkonium chloride, poloxamers, poly(oxyethylene) sorbitans, lecithin, pentadecalactone, methyl nicotinate, cholesterol, bile salts, lauric acid, oleic acid, valeric acid, isopropyl myristate, isopropyl palmitate, methylpropionate, ethyl oleate, propylene glycol, propylene glycol monolaurate, ethylene glycol, glycerol, butanediol, polyethylene glycol, polyethylene glycol monolaurate, phosphatidyl choline, phosphatidyl ethanolamine, dioleoylphosphatidyl choline, dioleoylphosphatidyl glycerol, dioleoylphoshatidyl ethanolamine, urea, dimethylacetamide, dimethylformamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine, triethanolamine, terpenes, alkanones, cyclodextrins, salicylic acid, citric acid, succinic acid, and combinations thereof.
11. The composition of claim 10, wherein the penetration enhancer is a cyclodextrin.
12. The composition of claim 11, wherein the cyclodextrin is selected from the group consisting of dimethyl-β-cyclodextrin, trimethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and combinations thereof.
13. The composition of claim 10, wherein the penetration enhancer is selected from the group consisting of cyclodextrins, isopropyl myristate, oleic acid, pentadecalactone, propylene glycol, propylene glycol monolaurate, triethanolamine, and combinations thereof.
14. The composition of claim 1, wherein the composition provides local anesthetic activity within about ten minutes of application of the composition to a patient's body surface
15. The composition of claim 1, wherein the polymer is hydrophilic and the composition is a hydrophilic gel.
16. The composition of claim 15, wherein the polymer is selected from the group consisting of poly(N-vinyl lactams), polyethylene glycol, poly(ethylene oxide-co-propylene oxide), polyvinyl alcohol, polyvinyl acetate, polylactide, poly(lactide-co-glycolide), polysorbate, poly(oxyethylated) glycerol, poly(oxyethylated) sorbitol, poly(oxyethylated) glucose, cellulosic polymers, carbomers, acrylamide-sodium acrylate copolymers, gelatin, alginates, pectins, carrageenans, xanthan gum, starches, galactomannans, acrylate polymers, and combinations thereof.
17. The composition of claim 16, wherein the polymer is selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, cellulosic polymers, acrylate polymers, carbomers, gelatin, alginates, pectins, carageenan, tragacanth, xanthan gum, starches, galactomannans, and combinations thereof.
18. The composition of claim 17, wherein the polymer is carrageenan.
19. The composition of claim 18, wherein the monohydric alcohol is lauryl alcohol, the penetration enhancer is comprised of a mixture of propylene glycol monolaurate and hydroxypropyl-β-cyclodextrin, and the local anesthetic agent is tetracaine.
20. The composition of claim 1, wherein the polymer is hydrophobic and the composition is a hydrophobic gel.
21. The composition of claim 20, wherein the polymer is selected from ethylene-propylene-styrene terpolymers, butylene-ethylene-styrene terpolymers, butyl rubber, natural rubber adhesives, vinyl ether polymers, polysiloxanes, polyisoprene, butadiene acrylonitrile rubber, polychloroprene, atactic polypropylene, and combinations thereof.
22. The composition of claim 20, wherein the polymer is selected from the group consisting of ethylene-propylene-styrene terpolymers, butylene-ethylene-styrene terpolymers, butyl rubber, and combinations thereof.
23. The composition of claim 22, further comprising an oil, a fatty acid ester or combination thereof.
24. The composition of claim 1, further comprising a pharmaceutically acceptable excipient.
25. The composition of claim 24, wherein the excipient is selected from the group consisting of antioxidants, stabilizers, surfactants, solvents, preservatives, pH regulators, softeners, colorants and combinations thereof.
26. The composition of claim 1, further comprising an additional active agent.
27. The composition of claim 26, wherein the additional active agent is selected from the group consisting of bacteriostatic and bactericidal compounds, antibiotic agents, topical vasodilators, tissue-healing enhancing agents, amino acids, proteins, proteolytic enzymes, cytokines, polypeptide growth factors and combinations thereof.
28. The pharmaceutical composition of claim 1, wherein the monohydric alcohol is selected to volatilize following application of the composition to a localized region of a patient's body surface, thereby forming a film within the localized region.
29. The composition of claim 28, wherein the monohydric alcohol is selected from the group consisting of methanol, ethanol, denatured ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, s-butyl alcohol, t-butyl alcohol, cyclohexanol, phenol, benzyl alcohol, pentanol, hexanol, menthol, and combinations thereof.
30. The composition of claim 35, wherein the volatile monohydric alcohol is selected from the group consisting of methanol, ethanol, denatured ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, s-butyl alcohol, t-butyl alcohol, and combinations thereof.
31. The composition of claim 28, wherein the monohydric alcohol represents about 40 wt. % to about 90 wt. % of the composition.
32. The composition of claim 28, wherein the film is water soluble.
33. The composition of claim 32, wherein the polymer is selected from the group consisting of hydroxypropyl cellulose, acrylate polymers, carbomers, gelatin, alginates, pectins, carrageenan, xanthan gum, starches, galactomannans, poly(N-vinyl lactams), and combinations thereof.
34. The composition of claim 33, wherein the polymer is a poly(N-vinyl lactam).
35. The composition of claim 34, wherein the poly(N-vinyl lactam) is selected from the group consisting of polyvinyl pyrrolidone, poly(N-vinyl caprolactam), and combinations thereof.
36. The composition of claim 28, wherein film is water insoluble.
37. The composition of claim 36, wherein the polymer is a cellulose ester.
38. The composition of claim 37, wherein the cellulose ester is selected from the group consisting of cellulose acetate butyrate, cellulose acetate, cellulose acetate phthalate, cellulose acetate propionate, and combinations thereof.
39. The composition of claim 36, wherein the polymer is a cellulose ether.
40. The composition of claim 39, wherein the cellulose ether is selected from the group consisting of ethyl cellulose, methyl cellulose, and combinations thereof.
41. The composition of claim 28, wherein the film is water resistant.
42. The composition of claim 41, wherein the polymer is a protein.
43. The composition of claim 42, wherein the protein is zein.
44. The composition of claim 28, further comprising a film-forming adjuvant.
45. The composition of claim 44, wherein the film-forming adjuvant is dimethylsiloxane, dimethylsulfoxide, or a combination thereof.
46. A method for administering a local anesthetic agent to a patient comprising topically administering to the patient's body surface a composition comprising (a) a therapeutically effective amount of a local anesthetic agent and (b) a pharmaceutically acceptable, nonliposomal carrier comprised of a monohydric alcohol, a penetration enhancer, and a polymer selected from the group consisting of hydrophilic polymers, hydrophobic polymers and combinations thereof, wherein local anesthetic activity is provided within about thirty minutes following topical administration.
47. The method of claim 46, wherein the local anesthetic activity is provided for at least 4 hours following topical administration.
48. The method of claim 46, wherein the local anesthetic activity is provided for at least 6 hours following topical administration.
49. The method of claim 46, wherein the monohydric alcohol is selected to volatilize following application of the composition to a localized region of a patients body surface, thereby forming a film within the localized region.
50. A drug delivery system for topical administration of a local anesthetic agent, wherein the system is in the form of a laminated composite comprising:
(a) a drug reservoir layer containing a pharmaceutical composition of (i) a therapeutically effective amount of a local anesthetic agent, (ii) a monohydric alcohol, and (iii) an effective enhancing amount of a penetration enhancer; and
(b) a backing layer laminated to the drug reservoir layer that serves as the outer surface of the system following application to a patient's body surface.
51. The system of claim 50, wherein the drug reservoir comprises a polymeric matrix of a pharmaceutically acceptable bioadhesive material that defines the basal surface of the system and serves to affix the device to a body surface.
52. The system of claim 50, further including a layer of a pharmaceutically acceptable bioadhesive material that defines the basal surface of the system and serves to affix the system to a body surface.
53. The system of claim 50, wherein the drug reservoir is comprised of a sealed compartment containing the pharmaceutical composition in a liquid or gel formulation.
54. The system of claim 50, further including a removable release liner covering the basal surface of the system prior to application to the patient's body surface.
55. The system of claim 50, wherein the drug reservoir layer is water soluble.
56. A method for administering a local anesthetic agent to a patient, comprising applying the drug delivery system of claim 50 to a predetermined region of the patient's body surface.
Descripción
    CROSS-REFERENCE TO RELATED APPLICATION
  • [0001]
    This application claims priority under 35 U.S.C. §119(e)(1) to U.S. Provisional Application Serial No. 60/289,403, filed May 7, 2001, the disclosure of which is incorporated by reference.
  • TECHNICAL FIELD
  • [0002]
    The invention relates generally to pharmaceutical compositions and drug delivery systems, and more particularly relates to pharmaceutical compositions and drug delivery systems for administration of an anesthetic agent, particularly a local anesthetic agent. In addition, the invention relates to methods for administering local anesthetic agents to patients using the aforementioned pharmaceutical compositions and drug delivery systems.
  • BACKGROUND
  • [0003]
    Anesthetic agents are widely used in the management of pain. Pharmacologically, most anesthetic agents reversibly block the conduction of pulses along nerve axons and other excitable membranes. Clinically, local administration of an anesthetic agent results in selective anesthesia, i.e., anesthesia limited to the area near the location of administration, and only for a limited quantity of time, e.g., on the order of four hours or less. Thus, local anesthetic agents derive their clinical usefulness and popularity by selectively, and reversibly, blocking noxious nerve impulses.
  • [0004]
    Administration of a local anesthetic agent can be used for a variety of purposes. For example, local anesthetic agents can be used to treat noxious stimuli caused by irritation from an environmental toxin, e.g., a toxic resin of a poisonous plant. Local anesthetic agents have also been used to treat the pain associated with wounds or tissue damage. Often, local anesthetic agents are administered to an individual undergoing a medical, dental or cosmetic procedure to treat the pain associated with such procedures. For these uses, the local anesthetic agent is often administered prior to undergoing the procedure so that any pain associated therewith is ameliorated or eliminated.
  • [0005]
    Cocaine, one of the first local anesthetic agents, possesses strong anesthetic properties and was initially used as an ophthalmic anesthetic agent. Although very effective in producing local anesthesia, cocaine's highly addictive nature was soon discovered and less-addictive alternatives were sought. Researchers synthesized new local anesthetic agents based on the chemical structure of cocaine. Currently, many local anesthetic agents are available that are non-addicting.
  • [0006]
    One drawback of local administration is that needles are often used to inject the drug, thereby causing pain to the patient. Often, the mere presence of a needle triggers anxiety, fear and discomfort. Gupta et al. (1996) J. Am. Acad. Dermatol. 35(3):419-423. This is particularly true for children and patients with a low pain threshold, making treatment of these individuals difficult. Ideally, administration of a local anesthetic agent should not be painful.
  • [0007]
    One approach for minimizing the pain associated with local administration of an anesthetic agent is the topical administration of the agent via a suitable delivery system, e.g., patch, or composition, e.g., cream, gel or ointment. Unlike direct injection, topical administration does not require the use of needles. In addition, topical administration does not require the expertise of a nurse or other skilled caregiver, thereby allowing for the ease and convenience of self-administration.
  • [0008]
    Topical administration, however, is not without drawbacks. For example, topical delivery of an anesthetic agent typically involves a delay prior to the onset of anesthesia. The delay is attributable to the time it takes for the anesthetic agent to reach the targeted tissue area. For example, EMLA® brand of lidocaine and prilocaine cream (AstraZeneca, Westborough, Mass.) is commonly applied sixty minutes before initiating a potentially painful dermal procedure. Riendeau et al. (1999) Reg. Anesth. Pain Med. 24(2):165-169. Such a delay can be inconvenient and may force some patients undergoing certain medical or cosmetic procedures to wait before the procedure can begin. Some have even suggested that clinics reorganize their procedures in order to accommodate such long waiting periods. Robieux et al. (1990) Can. J. Hosp. Pharm. 43(5):235-236. Clearly, it would be advantageous to have a topical formulation or device that would provide local anesthesia more quickly.
  • [0009]
    Another drawback commonly associated with topical administration of active agents is that the active agent may not penetrate into the deeper layers of the skin. This may be particularly problematic with a local anesthetic agent. For example, the cause of the pain may reside beneath the upper layers of the skin, beyond the reach of many conventional topical pain-relieving compositions. Thus, compositions and devices are desired that provide enhanced penetration of a topically administered local anesthetic agent.
  • [0010]
    Some have suggested using permeation enhancers to address the delayed onset of anesthesia and/or insufficient penetration of the active agent. U.S. Pat. No. 5,912,271 to Brodin et al. describes a composition comprising an anesthetic agent, a triacylglycerol, and one or more polar lipids. The described composition is stated to provide anesthesia in as little as fifteen minutes following application to a body surface. However, the triacylglycerol must be very pure and free from other glycerides. Such purity requires additional processing and testing steps, thereby increasing the complexity of the formulation.
  • [0011]
    U.S. Pat. No. 4,557,934 to Cooper describes the use of 1-dodecylazacycloheptan-2-one (commercially referred to as Azone®) as a penetration enhancer for local anesthetic agents and other drugs. Although this and other permeation enhancers may provide some measure of increased penetration, the need still exists for compositions and delivery systems for administering a local anesthetic agent that will have a relatively fast onset of action and be able to more deeply penetrate the skin. The present invention satisfies this and other needs in the art.
  • SUMMARY OF THE INVENTION
  • [0012]
    Accordingly, it is a primary object of the invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a local anesthetic agent in a pharmaceutically acceptable, nonliposomal carrier, wherein the nonliposomal carrier comprises a monohydric alcohol, a penetration enhancer, and a polymer selected from the group consisting of hydrophilic polymers, hydrophobic polymers and combinations thereof, wherein the local anesthetic activity is provided within about thirty minutes of application of the composition to a patient's body surface.
  • [0013]
    It is a further object of the invention to provide such a composition wherein the local anesthetic agent is selected from the group consisting of tetracaine, lidocaine, prilocaine, benzocaine, and combinations thereof.
  • [0014]
    It is still a further object of the invention to provide such a composition wherein the composition forms a water-soluble, water-insoluble, or water-resistant film upon application of the composition to a body surface of a patient.
  • [0015]
    It is a further object of the invention to provide such a composition in the form of a hydrophobic or hydrophilic gel.
  • [0016]
    It is a further object of the invention to provide a pharmaceutical composition comprising (a) a therapeutically effective amount of a local anesthetic agent and (b) a pharmaceutically acceptable, nonliposomal carrier comprised of a volatile monohydric alcohol, an effective enhancing amount of a penetration enhancer, and a polymer selected from the group consisting of hydrophilic polymers, hydrophobic polymers and combinations thereof, wherein the composition forms a film following application to a body surface of a patient and evaporation of the monohydric alcohol.
  • [0017]
    It is a further object of the invention to provide a drug delivery system for topical administration of a local anesthetic agent.
  • [0018]
    It is yet another object of the invention to provide a drug delivery system for mucosal administration of a local anesthetic agent.
  • [0019]
    A still further object of the invention is to provide a method for administering a local anesthetic agent to a patient by topically applying to the patient's body surface a pharmaceutical composition or drug delivery system as provided herein.
  • [0020]
    Additional objects, advantages and novel features of the invention will be set forth in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
  • [0021]
    In one embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a local anesthetic agent and a pharmaceutically acceptable, nonliposomal carrier that comprises a monohydric alcohol, an effective enhancing amount of a penetration enhancer, and a polymer selected from the group consisting of hydrophilic polymers, hydrophobic polymers and combinations thereof, wherein the carrier assists in providing local anesthetic activity within about thirty minutes of application of the composition to a patient's body surface. The local anesthetic agent is preferably blended with the carrier to form a consistent and homogenous admixture.
  • [0022]
    Depending on the polymer used and the relative amounts of the components in the nonliposomal carrier, the compositions can advantageously take one of several forms. For example, when a relatively large amount of a monohydric alcohol is present in the nonliposomal carrier, e.g., in the range of about 40 wt. % to about 90 wt. % based on the total weight of the composition, the composition forms a film following application to a body surface and concomitant and/or subsequent evaporation of the alcohol. Furthermore, depending on the polymer used, the film can be water soluble, water insoluble, or water resistant in nature. When a relatively smaller quantity of the monohydric alcohol is incorporated into the composition, e.g., less than about 40 wt. %, the composition forms a gel. Depending on the polymer used, the gel may be hydrophobic or hydrophilic.
  • [0023]
    In another embodiment, a drug delivery system is provided for topical administration of a local anesthetic agent. The system is a device in the form of a laminated composite having a drug reservoir layer containing a pharmaceutical composition and, optionally, an upper backing layer laminated to the drug reservoir layer. The pharmaceutical composition includes (i) a therapeutically effective amount of a local anesthetic agent, (ii) a monohydric alcohol, and (iii) an effective enhancing amount of a penetration enhancer. The backing layer, if present, serves as the outer surface of the device following application to a patient's body surface.
  • [0024]
    In still another embodiment, a drug delivery system is provided for mucosal administration of a local anesthetic agent. The system includes a drug reservoir layer that is water soluble; this is advantageous for buccal (or other transmucosal) drug delivery, wherein gradual and complete hydrolysis of the device in situ is desired. In this embodiment, the backing layer is absent, although the system may include a hydrophobic layer that serves as the outer surface of the device during use.
  • [0025]
    In yet another embodiment, a method is provided administering a local anesthetic agent to a patient. The method comprises applying a pharmaceutical composition or drug delivery system as provided herein to a localized region of the patient's body surface, e.g., the skin or mucosa.
  • [0026]
    Following application to a body surface, the compositions and delivery systems described herein provide immediate anesthesia to the desired tissues, i.e., local anesthesia occurs within about thirty minutes, preferably within about ten minutes, of application. In addition, the local anesthetic effect penetrates more deeply relative to conventional local anesthetic compositions and delivery systems. Finally, the anesthetic effect is generally prolonged relative to that obtained with conventional local anesthetic compositions and delivery systems, e.g., lasting at least 4 to 6 hours.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • [0027]
    [0027]FIG. 1. is a graph comparing the in vivo anesthesia achieved with an anesthetic gel of the invention and with the commercially available ELAMAX®5 brand of topical anesthetic cream, as described in Example 1.
  • [0028]
    [0028]FIG. 2. is a graph comparing the in vivo anesthesia achieved with an anesthetic gel of the invention and with the commercially available EMLA® brand of cream, as described in Example 2.
  • [0029]
    [0029]FIG. 3. is a graph comparing the in vivo anesthesia achieved with an anesthetic gel of the invention and with the commercially available APETOP® brand of topical anesthetic cream as described in Example 3.
  • DETAILED DESCRIPTION OF THE INVENTION I. Definitions and Nomenclature
  • [0030]
    Before describing the present invention in detail, it is to be understood that unless otherwise indicated this invention is not limited to specific local anesthetic agents, monohydric alcohols, penetration enhancers, polymers, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
  • [0031]
    It must be noted that, as used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a local anesthetic agent” includes a single local anesthetic agent as well as two or more local anesthetic agents, reference to “a polymer” includes a single polymer as well as combinations and mixtures of two or more polymers, and the like.
  • [0032]
    In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set forth below.
  • [0033]
    The terms “active agent,” “drug” and “pharmacologically” are used interchangeably herein to refer to a chemical material or compound that, when administered to a patient (human or animal) induces a desired pharmacologic effect. Included are derivatives and analogs of those compounds or classes of compounds specifically mentioned that also induce the desired pharmacologic effect. Unless the context clearly dictates otherwise, the active agents referred to herein are local anesthetic agents.
  • [0034]
    The term “crosslinked” refers to a composition containing intramolecular and/or intermolecular crosslinks, whether arising through covalent or noncovalent bonding. “Noncovalent” bonding includes both hydrogen bonding and electrostatic (ionic) bonding.
  • [0035]
    The term “polymer” includes linear and branched polymer structures, and also encompasses crosslinked polymers as well as copolymers (which may or may not be crosslinked), thus including block copolymers, alternating copolymers, random copolymers, and the like. Those compounds referred to herein as “oligomers” are polymers having a molecular weight below about 1000 Da, preferably below about 800 Da.
  • [0036]
    The term “hydrogel” is used in the conventional sense to refer to water-swellable polymeric matrices that can absorb a substantial amount of water to form elastic gels, wherein “matrices” are three-dimensional networks of macromolecules held together by covalent or noncovalent crosslinks. Upon placement in an aqueous environment, dry hydrogels swell to the extent allowed by the degree of cross-linking.
  • [0037]
    The term “topical administration” is used in its conventional sense to mean application of an active agent to the skin or mucosa to achieve a local effect, as in, for example, topical drug administration in the prevention or treatment of pain. Topical administration herein may include transdermal delivery as well as transmucosal delivery, wherein the active agent passes through the skin or mucosal tissue and ultimately enters a patient's bloodstream.
  • [0038]
    The term “body surface” is used to refer to skin or mucosal tissue, including the interior surface of body cavities that have a mucosal lining. Thus, the term “body surface” contemplates the skin surface, the surface of a wound, the mucosa of the oral cavity, the surfaces of the vagina, and so forth. The term “skin” should be interpreted as including “mucosal tissue” and vice versa, unless the context clearly indicates otherwise.
  • [0039]
    By a “pharmaceutically acceptable carrier” is meant a material that is suitable for transdermal drug administration to an individual along with an active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical formulation in which it is contained.
  • [0040]
    Similarly, a “pharmacologically acceptable” salt, ester, isomer or other derivative of an active agent as provided herein is a salt, ester, solvate, isomer or other derivative that is not biologically or otherwise undesirable.
  • [0041]
    By the terms “effective amount” and “therapeutically effective amount” of an active agent as provided herein is meant a nontoxic but sufficient amount of the agent to provide the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on the age, weight, and general condition of the subject, the severity of the condition being treated, the judgment of the clinician, and the like. Thus, it is not possible to specify an exact “effective amount.” However, an appropriate “effective amount” in any individual case may be determined by one of ordinary skill in the art using only routine experimentation.
  • [0042]
    The terms “treating” and “treatment” as used herein refer to the reduction in severity and/or frequency of symptoms and/or their underlying cause, and improvement or remediation of damage. Thus, for example, the present method of “treating” pain, as the term “treating” is used herein, encompasses both the prevention and initiation of a sensation of pain in the patient as well as the treatment of a patient experiencing pain.
  • [0043]
    The terms “condition,” “disease” and “disorder” are used interchangeably herein as referring to a physiological state that can be prevented or treated by administration of a composition or drug delivery device as described herein.
  • [0044]
    The term “patient” refers to a mammalian individual afflicted with or prone to a condition, disease or disorder as specified herein, and includes both humans and animals.
  • II. Anesthitic Compositions
  • [0045]
    A. ACTIVE AGENTS:
  • [0046]
    The active agent in the pharmaceutical compositions and drug delivery systems is a local anesthetic agent. Structurally, most local anesthetic agents contain a lipophilic group, e.g., an aromatic ring, a hydrocarbyl linking group (often having an amide or ester functionality), and an ionizable group, e.g., a tertiary amine. The invention, however, is not limited with respect to the molecular structure of the active agent.
  • [0047]
    Local anesthetic agents that can be administered using the compositions and drug delivery systems of the invention include, without limitation, acetamidoeugenol, alfadolone acetate, alfaxalone, amucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, burethamine, butacaine, butaben, butanilicaine, buthalital, butoxycaine, carticaine, 2-chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, diperadon, dyclonine, ecgonidine, ecgonine, ethyl aminobenzoate, ethyl chloride, etidocaine, etoxadrol, β-eucaine, euprocin, fenalcomine, fomocaine, hexobarbital, hexylcaine, hydroxydione, hydroxyprocaine, hydroxytetracaine, isobutyl p-aminobenzoate, kentamine, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methohexital, methyl chloride, midazolam, myrtecaine, naepaine, octacaine, orthocaine, oxethazaine, parethoxycaine, phenacaine, phencyclidine, phenol, piperocaine, piridocaine, polidocanol, pramoxine, prilocaine, procaine, propanidid, propanocaine, proparacaine, propipocaine, propofol, propoxycaine, pseudococaine, pyrrocaine, risocaine, salicyl alcohol, tetracaine, thialbarbital, thimylal, thiobutabarbital, thiopental, tolycaine, trimecaine, zolamine, and combinations thereof.
  • [0048]
    Preferred local anesthetic agents are tetracaine, lidocaine, prilocaine, benzocaine, and combinations thereof, with tetracaine and lidocaine most preferred.
  • [0049]
    The amount of the local anesthetic agent contained in the compositions and drug delivery systems herein is a therapeutically effective amount. The therapeutically effective amount will generally although not necessarily be in the range of about 0.1 wt. % to about 50 wt. %, more preferably about 0.1 wt. % to about 30 wt. %, and most preferably about 0.1 wt. % to about 10 wt. % based on the total weight of the composition.
  • [0050]
    The compositions and systems described herein may include one or more additional active agents. Although any additional active agent suitable for topical or transdermal administration may be used, preferred additional active agents are as follows:
  • [0051]
    Bacteriostatic and bactericidal agents: Suitable bacteriostatic and bactericidal agents include, by way of example: halogen compounds such as iodine, iodopovidone complexes (i.e., complexes of PVP and iodine, also referred to as “povidine” and available under the tradename Betadine® from Purdue Frederick), iodide salts, chloramine, chlorohexidine, and sodium hypochlorite; silver and silver-containing compounds such as sulfadiazine, silver protein acetyltannate, silver nitrate, silver acetate, silver lactate, silver sulfate and silver chloride; organotin compounds such as tri-n-butyltin benzoate; zinc and zinc salts; oxidants, such as hydrogen peroxide and potassium permanganate; aryl mercury compounds, such as phenylmercury borate or merbromin; alkyl mercury compounds, such as thiomersal; phenols, such as thymol, o-phenyl phenol, 2-benzyl-4-chlorophenol, hexachlorophen and hexylresorcinol; and organic nitrogen compounds such as 8-hydroxyquinoline, chlorquinaldol, clioquinol, ethacridine, hexetidine, chlorhexedine, and ambazone.
  • [0052]
    Antibiotic agents: Suitable antibiotic agents include, but are not limited to, antibiotics of the lincomycin family (referring to a class of antibiotic agents originally recovered from streptomyces lincolnensis), antibiotics of the tetracycline family (referring to a class of antibiotic agents originally recovered from streptomyces aureofaciens), and sulfur-based antibiotics, i.e., sulfonamides. Exemplary antibiotics of the lincomycin family include lincomycin itself (6,8 dideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)-carbonyl]amino]-1-thio-L-threo-α-D-galacto-octopyranoside), clindamycin, the 7-deoxy, 7-chloro derivative of lincomycin (i.e., 7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl]amino]-1-thio-L-threo-α-D-galacto-octopyranoside), related compounds as described, for example, in U.S. Pat. Nos. 3,475,407, 3,509,127, 3,544,551 and 3,513,155, and pharmacologically acceptable salts and esters thereof. Exemplary antibiotics of the tetracycline family include tetracycline itself 4-(dimethylamino)-1,4,4α,5,5α,6,11,12α-octahydro-3,6,12,12α-pentahydroxy-6-methyl-1,11 -dioxo-2-naphthacenecarboxamide), chlortetracycline, oxytetracycline, tetracycline, demeclocycline, rolitetracycline, methacycline and doxycycline and their pharmaceutically acceptable salts and esters, particularly acid addition salts such as the hydrochloride salt. Exemplary sulfur-based antibiotics include, but are not limited to, the sulfonamides sulfacetamide, sulfabenzamide, sulfadiazine, sulfadoxine, sulfamerazine, sulfamethazine, sulfamethizole, sulfamethoxazole, and pharmacologically acceptable salts and esters thereof, e.g., sulfacetamide sodium.
  • [0053]
    Topical Vasodilators: Such compounds are useful for increasing blood flow in the dermis, and preferred topical vasodilators are those known as rubefacients or counterirritants. Rubefacient agents include nicotinic acid, nicotinates such as methyl, ethyl, butoxyethyl, phenethyl and thurfyl nicotinate, as well as the essential oils such as mustard, turpentine, cajuput and capsicum oil, and components thereof. Particular preferred such compounds include, but are not limited to, methyl nicotinate, nicotinic acid, nonivamide, and capsaicin.
  • [0054]
    Proteolytic enzymes: Proteolytic enzymes include, for example, pepsin, trypsin, collagenase, chymotrypsin, elastase, carboxypeptidase, aminopeptidase, and the like.
  • [0055]
    Peptide, proteins, and amino acids: Suitable peptides and proteins are tissue-healing enhancing agents (also referred to in the art as “tissue regenerative agents”) such as collagen, glycosaminoglycans (e.g., hyaluronic acid, heparin, heparin sulfate, chondroitin sulfate, etc.), proteoglycans (e.g., versican, biglycan) substrate adhesion molecules (e.g., fibronectin, vitronectin, laminin), polypeptide growth factors (e.g., platelet-derived growth factor, a fibroblast growth factor, a transforming growth factor, an insulin-like growth factor, etc.), and other peptides such as fibronectin, vitronectin, osteopontin, and thrombospondin, all of which contain the tripeptide sequence RGD (arginine-glycine-aspartic acid), a sequence generally associated with adhesive proteins and necessary for interaction with cell surface receptors.
  • [0056]
    Salts, esters, amides, and derivatives of the active agent(s) may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure,” 4th Ed. (New York: Wiley-Interscience, 1992). For example, acid addition salts are prepared from the free base (e.g., compounds having a neutral -NH2 or cyclic amine group) using conventional means, involving reaction with a suitable acid. Typically, the base form of an active agent is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added at a temperature of about 0° C. to about 100° C., preferably at ambient temperature. The resulting salt either precipitates or may be brought out of solution by addition of a less polar solvent. Suitable acids for preparing the acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. An acid addition salt may be reconverted into the free base by treatment with a suitable base. Basic addition salts of an active agent having an acid moiety (e.g., carboxylic acid group or hydroxyl group) are prepared in a similar manner using a pharmaceutically acceptable base. Suitable bases include both inorganic bases, e.g., sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, and the like, as well as organic bases such as trimethylamine, or the like. Preparation of esters involves functionalization of hydroxyl and/or carboxyl groups that may be present within the molecular structure of the drug. The esters are typically acyl-substituted derivatives of free alcohol groups, i.e., moieties which are derived from carboxylic acids of the formula RCOOH where R is alkyl, and preferably is lower, i.e., C1, to C6, alkyl. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures. Preparation of amides and prodrugs can be carried out in an analogous manner. Other derivatives of the active agents may be prepared using standard techniques known to those skilled in the art of synthetic organic chemistry, or may be deduced by reference to the pertinent literature and texts.
  • [0057]
    The active agent may also be administered in the form of an isolated stereoisomer or enantiomer as individual stereoisomers or enantiomers may have unique or beneficial properties that make that individual isomer particularly suited for administration using the composition and drug delivery systems of the invention.
  • [0058]
    The amount of the additional active agent represents a therapeutically effective amount, and will of course vary depending on the particular additional agent, but will generally be in the range of about 0.1 wt. % to about 50 wt. %, more preferably about 0.1 wt. % to about 30 wt. %, and most preferably about 0.1 wt. % to about 10 wt. % of the composition.
  • [0059]
    B. The Carrier
  • [0060]
    In addition to the active agent the present compositions also include a pharmaceutically acceptable, nonliposomal carrier containing a monohydric alcohol, a penetration enhancer, and a polymer, as will be described in detail below. By “nonliposomal” is meant that the carrier is substantially free of liposomes. As is well known in the art, a liposome is a structure having a lipid bilayer that forms a microscopic sphere enclosing a liquid, e.g., aqueous, core. The bilayer is typically formed from phospholipids, although other materials may be used. While not wishing to be bound by theory, liposomal and other “barrier-forming” carriers are believed to delay the onset of anesthesia because the active agent has to penetrate through a membrane or wall, e.g., through the lipid bilayer of a liposome. In contrast, nonliposomal carriers have no such barrier preventing the active agent from directly contacting the target site, e.g., skin. It must be noted, however, that liposomal materials such as phospholipids can be present in the compositions so long as the composition is substantially free of liposomes per se. In this context, “substantially free of liposomes” is meant that less than about 40 wt. %, more preferably less than about 10 wt. %, of the active agent is encapsulated within liposomes.
  • [0061]
    Applicants have additionally found that the incorporation of a monohydric alcohol in a local anesthetic-containing composition provides the composition with superior performance characteristics. While not wishing to be bound by theory, applicants believe that the monohydric alcohol increases the carrier's overall solubilizing capacity while enhancing the penetration of the local anesthetic agent. Moreover, relatively large quantities of a monohydric alcohol result in film-forming compositions, such that an anesthetic-containing film is formed when the monohydric alcohol volatilizes.
  • [0062]
    Preferred monohydric alcohols include, without limitation, C1-C18 branched, linear, cyclic, saturated and unsaturated monohydric alcohols. Among unbranched monohydric alcohols, methanol, ethanol, denatured ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, dodecanol (i.e., lauryl alcohol), tridecanol, tetradecanol (i.e., myristyl alcohol), pentadecanol and hexadecanol (i.e., palmityl alcohol) are preferred. Other preferred monohydric alcohols include isopropyl alcohol, isobutyl alcohol, s-butyl alcohol, t-butyl alcohol, cyclohexanol, phenol, benzyl alcohol, and so forth. The monohydric alcohol can be optionally substituted with 1 to 4 substituents such as halo, lower alkoxy, thiol, and so on. Of course, combinations of any of the foregoing monohydric alcohols or additional alcohols may be included in the compositions and systems described herein.
  • [0063]
    The amount of monohydric alcohol in the composition is based, at least in part, on the type of formulation desired. Thus, for example, relatively lower amounts, i.e., in the range of about 1 wt. % to about 40 wt. %, are present in gel formulations. For film-forming compositions, the monohydric alcohol plays a role as a film-forming agent in the composition, in which case the composition may additionally contain other film-forming adjuvants such as dimethylsiloxane, dimethylsulfoxide or a combination thereof. For film-forming compositions, the monohydric alcohol is present in the composition in an amount of in the range of about 40 wt. % to about 90 wt. %. Preferably the amount of the film-forming agent is in the range of about 50 wt. % to about 80 wt. % of the composition.
  • [0064]
    For film-forming compositions, the volatility of the monohydric alcohol is such that upon application to a body surface, at least a fraction of the monohydric alcohol volatilizes. Consequently, when a film-forming composition is desired, the monohydric alcohol is preferably volatile, i.e., having a relatively low vapor pressure. Specifically, the vapor pressure of the monohydric alcohol in a film-forming composition is preferably less than about 75 kPa, more preferably less than about 50 kPa, and most preferably less than about 25 kPa at 25° C. As a lower limit, the vapor pressure of the monohydric alcohol in the film-forming composition will typically be higher than about 0.001 kPa at 25° C. Vapor pressures of monohydric alcohols can be determined experimentally or may be found in the relevant texts, e.g., CRC Handbook of Chemistry and Physics, 81 st Ed., Lide, Ed. (Boca Raton: CRC Press, 2000). Although most alcohols will have some degree of volatility, preferred monohydric alcohols in the film-forming compositions include methanol, ethanol, denatured ethanol, propanol alcohol, isopropyl alcohol, butanol, isobutyl alcohol, sec-butyl alcohol, t-butyl alcohol, cyclohexyl alcohol, phenol, benzyl alcohol, pentanol, hexanol, menthol, and combinations thereof. Of these, particularly preferred monohydric alcohols are the lower (C1-C4) monohydric alcohols, i.e., methanol, ethanol, denatured ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, s-butyl alcohol, t-butyl alcohol, and combinations thereof.
  • [0065]
    In order to provide enhanced penetration through the skin, the compositions and systems also include one or more penetration enhancers. Suitable enhancers include, for example, the following: sulfoxides such as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C10MSO); ethers such as diethylene glycol monoethyl ether (available commercially as Transcutol®) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, poloxamer (231, 182, 184), poly(oxyethylene) sorbitans, e.g., Tween® (20, 40, 60, 80) and lecithin (see, e.g., U.S. Pat. No. 4,783,450); pentadecalactone; methyl nicotinate; cholesterol; bile salts; fatty acids such as lauric acid, oleic acid and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methylpropionate and ethyl oleate; polyols and esters thereof such as propylene glycol, propylene glycol monolaurate, ethylene glycol, glycerol, butanediol, polyethylene glycol and polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); phospholipids such as phosphatidyl choline, phosphatidyl ethanolamine, dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG) and dioleoylphoshatidyl ethanolamine (DOPE); amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; cyclodextrins and substituted cyclodextrins such as dimethyl-β-cyclodextrin, trimethyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin; and organic acids, particularly salicylic acid and salicylates, citric acid, and succinic acid. Particularly preferred penetration enhancers herein are hydroxypropyl-βpcyclodextrin, isopropyl myristate, oleic acid, pentadecalactone, propylene glycol, propylene glycol monolaurate and triethanolamine. Combinations of any of the foregoing enhancers are contemplated as well.
  • [0066]
    The amount of the penetration enhancer in the composition is an effective enhancing amount. Generally an effective amount of an enhancer is in the range of about 0.1 wt. % to about 20 wt. %, more preferably from about 1 wt. % to about 10 wt. %, of the dry composition
  • [0067]
    The carrier also includes a polymer, and the type of polymer selected influences the characteristics and performance of the composition or drug delivery system. Hydrophobic gels will contain different polymers than hydrophilic gels, and water-soluble film-forming compositions will contain polymers other than those used in water-insoluble film-forming compositions. The polymers used in the present compositions and delivery systems include hydrophilic polymers, hydrophobic polymers and combinations thereof.
  • [0068]
    The definitions of “hydrophobic” polymers and “hydrophilic” polymers are based on the amount of water vapor absorbed by polymers at 100% relative humidity (“rh”). According to this classification, hydrophobic polymers absorb only up to 1 wt. % water at 100% rh, while moderately hydrophilic polymers absorb 1-10 wt. % water, hydrophilic polymers are capable of absorbing more than 10 wt. % of water, and hygroscopic polymers absorb more than 20 wt. % of water.
  • [0069]
    Gels are semisolid, suspension-type systems. Single-phase gels contain polymers distributed substantially uniformly throughout a carrier. In the present gel compositions, as discussed above, the amount of the monohydric alcohol is generally in the range of about 1 wt.% to about 40 wt. %. The type of gel, e.g., hydrophobic or hydrophilic, will largely depend upon the type of polymer used. In order to prepare a substantially uniform gel, the components of the carrier are thoroughly mixed, followed by addition of the active agent, which is then blended with the carrier.
  • [0070]
    Examples of suitable hydrophilic polymers used in hydrophilic gels of the invention include, but are not limited to: poly(N-vinyl lactams) such as polyvinyl pyrrolidone, poly(N-vinyl-2-valerolactam), and N-vinyl-2-caprolactam (optionally copolymerized with one or more second monomers such as N,N-dimethylacrylamide, acrylic acid, methacrylic acid, hydroxyethylmethacrylate, acrylamide, 2-acrylamido-2-methyl-1-propane sulfonic acid, and vinyl acetate); polyethylene glycol; poly(ethylene oxide-co-propylene oxide); polyvinyl alcohol; polyvinyl acetate; polylactide; poly(lactide-co-glycolide); polysorbate; poly(oxyethylated) glycerol; poly(oxyethylated) sorbitol; poly(oxyethylated) glucose; cellulosic polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose; carbomers, i.e., hydroxylated vinylic polymers also referred to as “interpolymers,” which are prepared by crosslinking a monoolefinic acrylic acid monomer with a polyalkyl ether of sucrose (commercially available under the trademark Carbopol® from the B. F. Goodrich Chemical Company); acrylamide-sodium acrylate copolymers; gelatin; vegetable polysaccharides, such as alginates, pectins, carrageenans, or xanthan gum; starch and starch derivatives; galactomannan and galactomannan derivatives; and acrylate polymers, generally formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, and/or other vinyl monomers. Suitable acrylate polymers are those copolymers available under the tradename “Eudragit” from Rohm Pharma (Germany). Preferred acrylate polymers are copolymers of methacrylic acid and methyl methacrylate, such as the Eudragit L and Eudragit S series polymers.
  • [0071]
    Preferred polymers for providing hydrophilic gels are the following: poly(N-vinyl lactams), particularly polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; cellulosic polymers; acrylate polymers; carbomers; gelatin; alginates; pectins; carageenan; tragacanth; xanthan gum; starches; and galactomannans, with carageenans particularly preferred. As used herein, the term “carrageenan” means a mixture of sulfated polysaccharides extracted from red seaweed (Rhodophyceae) having the ability to form gels. Carrageenan has been used extensively in the food industry and is available from commercial suppliers such as FMC Corp. (Philadelphia, Pa.).
  • [0072]
    The composition forms a hydrophobic or oily gel when the polymer in the composition is hydrophobic in nature. Hydrophobic polymers include, by way of example, butyl rubber, which, as well known in the art, is an isoprene-isobutylene copolymer typically having an isoprene content in the range of about 0.5 to 3 wt. %, or a vulcanized or modified version thereof, e.g., a halogenated (brominated or chlorinated) butyl rubber. A preferred polymer is butyl rubber crosslinked with polyisobutylene. Other suitable hydrophobic polymers include, by way of example and not limitation, ethylene-propylene-styrene terpolymers, butylene-ethylene-styrene terpolymers, natural rubber adhesives, vinyl ether polymers, polysiloxanes, polyisoprene, butadiene acrylonitrile rubber, polychloroprene, atactic polypropylene, ethylene-propylene-diene terpolymers (also known as “EPDM” or “EPDM rubber”) (available as Trilenee® 65 and Trilene® 67 from Uniroyal Chemical Co., Middlebury, Conn.), and butylene-ethylene-diene terpolymers. Particularly preferred hydrophobic polymers are ethylene-propylene-styrene terpolymers, butylene-ethylene-styrene terpolymers, and butyl rubber.
  • [0073]
    Additionally, the hydrophobic gel compositions preferably include an oil, a fatty acid ester, or both. The addition of an oil and/or fatty acid ester enhances the hydrophobicity of the gel without affecting the stability of the gel. As the amount of the oil and/or fatty acid ester in the composition increases, so does the hydrophobicity of the composition.
  • [0074]
    The oil may be naturally occurring, of vegetable, mineral or animal origin, or synthetic, and may be a single oil or comprised of a mixture of oils. Vegetable oils are derived from various plants and are generally produced by extraction or pressing processes, and include castor oil, linseed oil, sunflower oil, soybean oil, olive oil, peanut oil, rapeseed oil, corn oil, safflower oil, cottonseed oil, coconut oil, palm oil, palm kernel oil, etc. Mineral oils are derived from petroleum and are recovered through various refining processes, and include white mineral oil, paraffin oil, petrolatum and the like. Animal oils are derived from the organs and tissues of animals and may be collected through extraction, heating and/or expressing processes, and include lanolin, fatty acid esters, fish oil, whale oil, fish liver oil, seal oil, squalene, and so forth. Synthetic oils include silicone oils, e.g., dimethylpolysiloxane, cyclic silicones, methylphenyl-polysiloxane, etc. It is particularly preferred that the oil, when present, is a mineral oil. Any combination of oils may be used as well.
  • [0075]
    The fatty acid ester is typically a lower alkyl ester of a C8 to Cl8 fatty acid. Although any fatty acid ester may be used, preferred fatty acid esters are ethyl caprate, ethyl caprylate, ethyl oleate, ethyl laurate, ethyl linoleate, ethyl myristate, ethyl palmitate, ethyl stearate, isopropyl caprate, isopropyl caprylate, isopropyl oleate, isopropyl laurate, isopropyl linoleate, isopropyl myristate, isopropyl palmitate, butyl caprate, butyl caprylate, butyl oleate, butyl laurate, butyl linoleate, butyl myristate, butyl palmitate, and butyl stearate. A particularly preferred fatty acid ester is isopropyl palmitate.
  • [0076]
    As described herein, some of the present compositions, when placed on a body surface, will form a film containing the local anesthetic agent. Less bulky and more discreet than patches, the films obtained from these compositions still provide effective topical administration of a local anesthetic agent. Furthermore, the monohydric alcohol and any other solvents that may be present (e.g., water, acetone, and so forth) appear to initially enhance penetration, providing a rapid onset of anesthesia before evaporating completely. The film-forming composition can advantageously be sprayed onto skin using conventional means, e.g., an atomizer, spray bottle, or pressurized can, thereby avoiding direct contact with the body surface. The film-forming composition can be applied manually as well. Generally, although not necessarily, the film forms within about fifteen minutes, more preferably within about five minutes and most preferably within about one minute of application to the body surface. Moreover, the film that is formed has a thickness of from about 0.01 mm to about 2 mm, with a thickness of from about 0.1 to about 1 mm being preferred.
  • [0077]
    The polymer used in water-soluble, film-forming compositions may be any polymer that will form a water-soluble film following application of the composition to a body surface. A water-soluble film can be removed easily with the application of water and gentle agitation. Among other advantages, water-soluble films are easily removable, thereby providing a facile method for removing the film and subsequently discontinuing treatment.
  • [0078]
    Preferred polymers for water-soluble, film-forming compositions generally include the hydrophilic polymers set forth above, providing that the resulting composition forms a water-soluble film upon evaporation of water and any other solvents that may be present. Such polymers include, for example, certain cellulosic polymers, e.g., hydroxypropyl cellulose; acrylate polymers; carbomers; gelatin; alginates; pectins; carrageenan; xanthan gum; starches; galactomannans; and poly(N-vinyl lactams), e.g., polyvinyl pyrrolidone and poly(N-vinyl caprolactam). Particularly preferred polymers for use in the water-soluble, film-forming compositions are poly(N-vinyl lactams). In addition, combinations of any of the foregoing may be used.
  • [0079]
    Water-insoluble film-forming compositions include a polymer that will form a water-insoluble film upon application of the composition to a body surface. One advantage of water-insoluble films is that they resist removal, even with application of copious amounts of water and agitation. Accordingly, these films remain in place even in the presence of aqueous liquids such as sweat. Preferred polymers for use in compositions that form water-insoluble films generally include the hydrophobic polymers discussed above so long as the resulting composition forms a water-insoluble film upon evaporation of water and any other solvents that may be present. Preferred polymers, in this embodiment, are cellulose esters, e.g., cellulose acetate butyrate, cellulose acetate, cellulose acetate phthalate, and cellulose acetate propionate, and cellulose ethers, e.g., ethyl cellulose and methyl cellulose. Combinations of the polymers may also be used.
  • [0080]
    Water-resistant films may also be obtained from the present compositions. “Water-resistant” films are those films that are only partially resistant to removal with water and gentle agitation. The polymer in this embodiment is preferably a polymer of an amino acid. Thus, preferred polymers are proteins, with zein, a corn protein, being particularly preferred.
  • [0081]
    Other suitable hydrophobic and hydrophilic polymers can also be used in the film-forming compositions, and the invention is not limited in this regard. Any particular polymer can be tested for suitability in a film-forming composition of the invention by preparing a composition using the polymer of interest along with the other components, e.g., the monohydric alcohol, anesthetic agent, penetration enhancer, and so forth, and determining whether a film forms following application to a body surface. Moreover, the type of film formed, e.g., a water-soluble film, a water-insoluble film or water-resistant film, can be readily determined by detecting substantially all, some, or substantially none of the film following gentle agitation and washing with water.
  • [0082]
    All of the components of the compositions described herein (including the compositions used in the systems) are commercially available or may be readily synthesized from commercially available materials. For example, in the hydrophobic gel, a mixture of mineral oil, ethylene-propylene-styrene copolymer, and butylene-ethylene-styrene copolymer is available under the tradename Versagel® M (Penreco, Karns City, Pa.). In addition, a mixture of isopropyl palmitate, ethylene-propylene-styrene copolymer, and butylene-ethylene-styrene copolymer is available under the tradename Versagel® MP (Penreco, Karns City, Pa.).
  • [0083]
    The compositions described herein (including the compositions incorporated in drug delivery systems) may also contain one or more pharmaceutically acceptable excipients. Preferred excipients include plasticizers, antioxidants, stabilizers, surfactants, solvents, preservatives, pH regulators, softeners, thickeners, colorants or a combination thereof. Any additives should not significantly interfere with the desired chemical and physical properties of the composition or delivery system in which they are contained.
  • [0084]
    Incorporation of an antioxidant is optional but preferred. The antioxidant serves to enhance the oxidative stability of the composition. Heat, light, impurities, and other factors can all result in oxidation of the components of the composition. Thus, ideally, antioxidants should protect against light-induced oxidation, chemically induced oxidation, and thermally induced oxidative degradation during processing and/or storage. Oxidative degradation, as will be appreciated by those in the art, involves generation of peroxy radicals, which in turn react with organic materials to form hydroperoxides. Primary antioxidants are peroxy free radical scavengers, while secondary antioxidants induce decomposition of hydroperoxides, and thus protect a material from degradation by hydroperoxides. Most primary antioxidants are sterically hindered phenols, and preferred such compounds for use herein are tetrakis [methylene (3,5-di-tert-butyl-4-hydroxyhydrocinnamate)] methane (e.g., Irganox® 1010, from Ciba-Geigy Corp., Hawthorne, N.Y.) and 1,3,5-trimethyl-2,4,6-tris [3,5-di-t-butyl-4-hydroxy-benzyl] benzene (e.g., Ethanox® 330, from Ethyl Corp.). A particularly preferred secondary antioxidant that may replace or supplement a primary antioxidant is tris(2,4-di-tert-butylphenyl)phosphite (e.g., Irgafos® 168, Ciba-Geigy Corp.). Other antioxidants, including but not limited to multi-functional antioxidants, are also useful herein. Multifunctional antioxidants serve as both a primary and a secondary antioxidant. Irganox® 1520 D, manufactured by Ciba-Geigy is one example of a multifunctional antioxidant. Vitamin E antioxidants, such as that sold by Ciba-Geigy as Irganox® E17, are also useful in the present composition. Other suitable antioxidants include, without limitation, ascorbic acid, ascorbic palmitate, tocopherol acetate, propyl gallate, butylhydroxyanisole (BHA), butylated hydroxytoluene (BHT), bis(1,2,2,6,6-pentamethyl-4-piperidinyl)-(3,5-di-tert-butyl-4-hydroxybenzy l)butylpropanedioate, (available as Tinuvin®144 from Ciba-Geigy Corp.) or a combination of octadecyl 3,5-di-tert-butyl-4-hydroxyhydro-cinnamate (also known as octadecyl 3-(3′,5′-di-tert-butyl-4′-hydroxyphenyl)propionate) (available as Naugard® 76 from Uniroyal Chemical Co., Middlebury, Conn.) and bis(1,2,2,6,6-pentamethyl-4-piperidinylsebacate) (available as Tinuvin®765 from Ciba-Geigy Corp.). Preferably, the antioxidant is present in amount up to about 2 wt. % of the composition; typically, the amount of antioxidant is in the range of about 0.05 wt. % to 1.5 wt.%.
  • [0085]
    Preservatives serve to at least partially inhibit the growth of microbes. Preservatives include, by way of example, p-chloro-m-cresol, phenylethyl alcohol, phenoxyethyl alcohol, chlorobutanol, 4-hydroxybenzoic acid methylester, 4-hydroxybenzoic acid propylester, benzalkonium chloride, cetylpyridinium chloride, chlorohexidine diacetate or gluconate, ethanol, and propylene glycol.
  • [0086]
    Compounds useful as pH regulators include, but are not limited to, glycerol buffers, citrate buffers, borate buffers, phosphate buffers, or citric acid-phosphate buffers may also be included so as to ensure that the pH of the hydrogel composition is compatible with that of an individual's body surface. Solutions of acids and bases, e.g., a solution of sodium hydroxide, can be used to bring pH of the desired composition to a suitable range. In particular, the solution of sodium hydroxide (0.075M) can be used to bring the pH of present compositions to about 9.0. It is believed that compositions having a pH about 9.0 or higher do not require additional antimicrobial preservatives.
  • [0087]
    Suitable softeners include, by way of example, the following: citric acid esters, such as triethylcitrate or acetyl triethylcitrate; tartaric acid esters such as dibutyltartrate; glycerol esters such as glycerol diacetate and glycerol triacetate; phthalic acid esters such as dibutyl phthalate and diethyl phthalate; and/or hydrophilic surfactants, preferably hydrophilic non-ionic surfactants, such as, for example, partial fatty acid esters of sugars, polyethylene glycol fatty acid esters, polyethylene glycol fatty alcohol ethers, and polyethylene glycol sorbitan-fatty acid esters.
  • III. Drug Delivery Systems
  • [0088]
    The invention also provides a drug delivery system for topical administration of a local anesthetic agent. In one embodiment, the system is a device in the form of a laminated composite comprising: (a) a drug reservoir layer containing a pharmaceutical composition of (i) a therapeutically effective amount of a local anesthetic agent, (ii) a monohydric alcohol, and (iii) an effective enhancing amount of a penetration enhancer; and (b) a backing layer laminated to the drug reservoir layer that serves as the outer surface of the device following application to a patient's body surface.
  • [0089]
    In the manufacture of such systems, the reservoir layer may be cast or extruded onto a backing layer or release liner of such a system and serves as the skin contacting face of the “patch.” Alternatively, the drug reservoir layer may be contained within the system, with a conventional bioadhesive laminated thereto.
  • [0090]
    The drug reservoir layer contains a quantity of a local anesthetic agent effective to provide the desired dosage over a predetermined delivery period. The drug reservoir layer optionally contains excipients such as colorants, thickening agents, stabilizers, surfactants and the like. Reference is made to the discussion of local anesthetic agents, penetration enhancers, and optional excipients discussed above.
  • [0091]
    The drug reservoir layer can be a polymeric matrix of a pharmaceutically acceptable bioadhesive material that provides the means to affix the system to a body surface. In such a case, the device is “monolithic,” meaning that a single layer serves as both the drug reservoir and the bioadhesive. Alternatively, the bioadhesive material may be an additional layer defining the basal surface of the device. The drug reservoir may also be comprised of a hydrogel. The drug reservoir can also be a sealed compartment containing the pharmaceutical local anesthetic agent and other components in a liquid or gel formulation. Optionally, more than one drug reservoir layer can be present, each layer containing the same active agent or a different active agent.
  • [0092]
    The backing layer functions as the primary structural element of the system and preferably provides flexibility as well as protection of the underlying system. The material used for the backing layer should be inert and incapable of absorbing drug, enhancer or other components of the composition. Also, the material used for the backing layer should permit the system to follow the contours of the body surface and be worn comfortably. For example, the material should permit the device to be used on areas of skin such as at joints or other points of flexure that are normally subjected to mechanical strain with little or no likelihood of the device disengaging from the skin due to differences in the flexibility or resiliency of the skin and the device. Examples of materials useful for the backing layer are polyesters, polyethylene, polypropylene, polyurethanes and polyether amides. The layer is preferably in the range of about 15 microns to about 250 microns in thickness, and may, if desired, be pigmented, metallized, or provided with a matte finish suitable for writing. The layer is preferably although not necessarily nonocclusive (or “breathable”), i.e., is preferably permeable to moisture.
  • [0093]
    Additional layers, e.g., intermediate fabric layers and/or rate-controlling membranes, may also be present. Fabric layers may be used to facilitate fabrication, while a rate-controlling membrane may be used to control the rate at which a component permeates out of the device. The component may be a drug, a penetration enhancer, or some other component contained in the drug delivery system.
  • [0094]
    In these systems, it may be desirable to include a rate-controlling membrane in the system on the body surface side of the drug reservoir. The materials used to form such a membrane are selected to limit the flux of one or more components contained in the drug formulation, and the membrane may be either microporous or dense. Representative materials useful for forming rate-controlling membranes include polyolefins such as polyethylene and polypropylene, polyamides, polyesters, ethylene-ethacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl methylacetate copolymer, ethylene-vinyl ethylacetate copolymer, ethylene-vinyl propylacetate copolymer, polyisoprene, polyacrylonitrile, ethylene-propylene copolymer, polysiloxane-polycarbonate block copolymer and the like.
  • [0095]
    For adhesive purposes, an acceptable bioadhesive material may be present in the drug reservoir or in a separate layer. Preferred adhesive materials include crosslinked polyisobutylene, butyl rubber, natural rubber adhesives, vinyl ether polymers, polysiloxanes, polyisoprene, butadiene acrylonitrile rubber, polychloroprene, atactic polypropylene, ethylene-propylene-diene terpolymers, and combinations thereof. Other suitable adhesives will be known to those of ordinary skill in the art and/or are described in the pertinent texts and literature. See, for example, the Handbook of Pressure-Sensitive Adhesive Technology, 2 nd Ed., Satas, Ed. (New York: Von Nostrand Reinhold, 1989).
  • [0096]
    The invention also provides a drug delivery system for administration of a local anesthetic agent to a mucosal surface, wherein the system comprises: (a) a water-soluble drug reservoir layer containing a pharmaceutical composition of (i) a therapeutically effective amount of a local anesthetic agent, (ii) a monohydric alcohol, (iii) an effective enhancing amount of a penetration enhancer and (iv) a polymer; and (b) an optional hydrophobic layer that serves as the outer surface of the device following application to the mucosal surface.
  • [0097]
    The various components of the system are as described above, providing that the drug reservoir is water soluble and that the system is preferably composed of a single layer (not including a release liner).
  • [0098]
    The drug delivery system for mucosal administration will preferably be used for buccal delivery, but the system may be applied to any mucosal surface for which local anesthesia is desired. Particularly for buccal delivery, the local anesthetic agent may be released from the system into the general region of the oral cavity, thereby reaching not only the area where the system is applied, but also areas proximal to the site of application. Although any polymer may be used that is suited for transmucosal delivery, preferred polymers are poly(N-vinyl lactams), particularly polyvinyl pyrrolidone and poly(N-vinyl caprolactam), polyethylene glycol, and combinations thereof.
  • [0099]
    Optionally, the transmucosal system includes a hydrophobic, water-resistant layer, which may or may not contain an active agent. The hydrophobic layer preferably, although not necessarily, comprises a cellulose ester such as cellulose acetate butyrate, cellulose acetate, cellulose acetate phthalate, cellulose acetate propionate, and combinations thereof.
  • IV. Utility and Administration
  • [0100]
    The invention also provides a method for administering a local anesthetic agent to a patient to treat or prevent pain. The method involves topically administering a pharmaceutical composition as described herein. The present method may be used to treat patients suffering from oral pain, including, but not limited to, a cold sore, canker sore, gum sore, gum injury, tooth ache, cough, sore throat or a combination thereof. Additionally, the method may be used to treat patients suffering from pain associated with a skin condition or disorder, e.g., an insect bite, muscle pain, arthritis, allergic reaction, rash (e.g., a rash caused by poison oak or poison ivy), itch, blister, sore nail, corn, mechanical puncture (e.g., catheterization and needle injection), laser treatment, or any combination thereof.
  • [0101]
    The method may also be used to treat patients suffering from breakthrough pain, migraine, neuropathic pain, and anginal pain. In addition, the compositions and systems of the invention may be administered with a wound dressing to treat burns, wounds and scrapes.
  • [0102]
    Advantageously, the compositions and drug delivery systems described herein can also be used as part of a pre-treatment regimen used to prevent or minimize the pain associated with other topical therapies, medical procedures or cosmetic procedures.
  • [0103]
    The compositions and drug delivery systems described herein have many advantages. Anesthesia is provided quickly, within about 15 to 30 minutes following application. Furthermore, penetration of the local anesthetic agent is enhanced, e.g., the local anesthetic agent can penetrate at least about 5 mm into the body surface. In addition, depending upon the anesthetic agent used, effective anesthesia can be maintained for at least 4 hours, and more preferably at least 6 hours.
  • [0104]
    The amount of the active agent administered depends upon the age, weight, and general condition of the subject, the severity of the condition being treated, and the judgment of the prescribing physician or attending clinician. Therapeutically effective amounts will be known to those skilled in the art and/or are described in the pertinent reference texts and literature. An effective amount of the composition may be administered by placing an appropriate amount, e.g., about 0.1 g to about 5 g of the composition, to the affected area. Alternatively, when a drug delivery system is used, the system will contain the effective amount and may applied to the affected area.
  • [0105]
    Generally, the effective amount will be in the range of about 0.01 mg to about 100 mg, more preferably about 0.1 mg to about 25 mg, and most preferably about 0.1 mg to about 10 mg of the active agent. Administration of the active agent can be carried out once, twice, three times or four times daily. Alternatively, or in addition to regularly scheduled doses, administration may be carried out on an “as needed” basis, or using a drug delivery system adapted to provide sustained drug delivery over an extended time period. The total daily dose, however, should generally not exceed about 5,000 mg of the active agent.
  • [0106]
    It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the foregoing description as well as the examples that follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.
  • [0107]
    All patents, patent applications and publications mentioned herein are hereby incorporated by reference in their entireties.
  • V. Experimental
  • [0108]
    The practice of the invention will employ, unless otherwise indicated, conventional techniques of pharmaceutical formulating and the like, which are within the skill of the art. Such techniques are fully explained in the literature. See for, example, Remington: The Science and Practice of Pharmacy, Twentieth Edition (Easton, Pa.: Mack Publishing Co., 2000).
  • [0109]
    In the following examples, efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.) but some experimental error and deviation should be accounted for. Unless otherwise indicated, temperature is in degrees C and pressure is at or near atmospheric pressure at sea level. All reagents and formulation components were obtained commercially unless otherwise indicated.
  • EXAMPLE 1
  • [0110]
    A pin-prick model was used to evaluate the efficacy of a carrageenan-based gel according to the present invention against the ELA-MAX® 5 brand of topical anesthetic cream, a cream commercially available from Ferndale Laboratories, Ferndale Minn. For each of the tested 10, 30, 60 and 180 time intervals, 0.025 g of formulation was applied to a 2 cm2 area on the ventral forearm of healthy volunteers. The formulation was allowed to remain in place until administration of the pin pricks at the tested time interval (i.e., 10, 20, 60 or 180 minutes), and was then removed from the forearm immediately prior to the administration of the pin pricks. A fifth series of pin pricks was administered at 60 minutes following the 180 minute interval, thereby providing data at 240 minutes. The pin used to administer the pricks has a diameter of 0.2 mm and a length of 1 mm. As a control, an untreated site on the ventral forearm was also pricked with the pin.
  • [0111]
    The ELA-MAX®5 brand of topical anesthetic cream contains lidocaine (5%) and uses a liposomal delivery system. The components of the carrageenan-based gel used in the example are provided in Table 1.
    TABLE 1
    Components of the Carrageenan-Based Gel
    Component Amount (wt. %)
    Carrageenan 3%
    Tetracaine 2%
    Hydroxypropyl-β-cyclodextrin 2%
    Lauryl alcohol 2%
    Propylene glycol monolaurate 2%
    pH 9 solution (NaOH O.075 M) q.s. to 100%
  • [0112]
    The carrageenan-based gel was prepared using conventional techniques. Briefly, the carrageenan, tetracaine, hydroxypropyl-β-cyclodextrin, lauryl alcohol, and propylene glycol monolaurate were measured, combined, and thoroughly mixed. Thereafter, a pH 9 solution (NaOH 0.075M) was added in amount sufficient to bring the total to 100%.
  • [0113]
    At untreated sites, 100% of the pin pricks were felt as painful. As demonstrated in FIG. 1, the anesthesia achieved by the carrageenan-based gel (a hydrophilic carrier) was dramatically higher than that of the commercially available ELA-MAX®5 brand of topical anesthetic cream.
  • EXAMPLE 2
  • [0114]
    The procedure of Example 1 was repeated except that EMLA® brand of topical cream was used in place of ELA-MAX®5 brand of topical anesthetic cream. The EMLA® brand of topical cream was obtained from AstraZeneca, Wilmington Del. As described in the packaging provided by the manufacturer, each gram of EMLA® brand of topical cream contains lidocaine (25 mg), prilocaine (25 mg), polyoxyethylene fatty acid esters, carboxypolymethylene, sodium hydroxide and purified water.
  • [0115]
    At untreated sites, 100% of the pin pricks were felt as painful. As demonstrated in FIG. 2, the anesthesia achieved by the carrageenan-based gel (a hydrophilic carrier) was dramatically higher than that of the commercially available EMLA®5 brand of topical cream.
  • EXAMPLE 3
  • [0116]
    The procedure of Example 1 was repeated except that AMETOP® brand of topical anesthetic cream was used in place of ELA-MAX5 brand of topical anesthetic cream. The AMETOP® brand of topical anesthetic cream was obtained from Smith and Nephew, London, United Kingdom.
  • [0117]
    At untreated sites, 100% of the pin pricks were felt as painful. As demonstrated in FIG. 3, the anesthesia achieved by the carrageenan-based gel (a hydrophilic carrier) was dramatically higher than that of the commercially available AMETOP® brand of topical anesthetic cream.
  • EXAMPLE 4
  • [0118]
    Propylene glycol (3 gm) and 10 grams of polyvinyl pyrrolidone are dissolved and mixed with 70 ml of ethanol. Ten grams of lidocaine are then added and mixed to form a film-forming composition. Upon application to a body surface, the composition forms a film and alleviates the pain associated with a wound. When washed with water, the film is easily removed.
Citas de patentes
Patente citada Fecha de presentación Fecha de publicación Solicitante Título
US4091090 *10 Dic 197623 May 1978Johnson & JohnsonPotentiated anesthetics
US4529601 *26 Ago 198216 Jul 1985Astra Lakemedel AktiebolagLocal anesthetic mixture for topical application and method for obtaining local anesthesia
US4557934 *21 Jun 198310 Dic 1985The Procter & Gamble CompanyPenetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one
US4562060 *11 Feb 198531 Dic 1985Astra Lakemedel AktiebolagLocal anesthetic mixture for topical application, process for its preparation, as well as method for obtaining local anesthesia
US4927408 *3 Oct 198822 May 1990Alza CorporationElectrotransport transdermal system
US4945084 *8 Jul 198731 Jul 1990Norman OksmanMethod and composition for topically treating anorectal or other dermal wounds
US5057500 *12 Feb 199015 Oct 1991Dermatologic Research CorporationTreatment of pruritis with esters and amides
US5196405 *27 Feb 199023 Mar 1993Norman H. OskmanCompositions and methods of treating hemorrhoids and wounds
US5234957 *23 Dic 199110 Ago 1993Noven Pharmaceuticals, Inc.Compositions and methods for topical administration of pharmaceutically active agents
US5322689 *10 Mar 199221 Jun 1994The Procter & Gamble CompanyTopical aromatic releasing compositions
US5332576 *21 May 199326 Jul 1994Noven Pharmaceuticals, Inc.Compositions and methods for topical administration of pharmaceutically active agents
US5446070 *27 Ago 199329 Ago 1995Nover Pharmaceuticals, Inc.Compositions and methods for topical administration of pharmaceutically active agents
US5543148 *12 Jul 19946 Ago 1996Combe, IncorporatedStick delivery system for topical application of a treatment agent
US5563153 *22 Feb 19958 Oct 1996University Of Kansas Medical CenterSterile topical anesthetic gel
US5614178 *27 Jun 199425 Mar 1997The Procter & Gamble CompanyCompositions for topical delivery of drugs comprising a mixture of high and low HLB surfactants and alkoxylated ether
US5631267 *20 Mar 199620 May 1997Mayo Foundation For Medical Education & ResearchMethod for the treatment of eosinophil-associated diseases by administration of topical anesthetics
US5719197 *7 Jun 199517 Feb 1998Noven Pharmaceuticals, Inc.Compositions and methods for topical administration of pharmaceutically active agents
US5744155 *13 Ago 199328 Abr 1998Friedman; DoronBioadhesive emulsion preparations for enhanced drug delivery
US5785976 *12 Abr 199428 Jul 1998Pharmacia & Upjohn AbSolid lipid particles, particles of bioactive agents and methods for the manufacture and use thereof
US5837713 *26 Feb 199717 Nov 1998Mayo Foundation For Medical Education And ResearchTreatment of eosinophil-associated pathologies by administration of topical anesthetics and glucocorticoids
US5853755 *10 Jun 199729 Dic 1998Pharmaderm Laboratories Ltd.Biphasic multilamellar lipid vesicles
US5858410 *9 Nov 199512 Ene 1999Medac Gesellschaft Fur Klinische SpezialpraparatePharmaceutical nanosuspensions for medicament administration as systems with increased saturation solubility and rate of solution
US5900249 *9 Feb 19984 May 1999Smith; David J.Multicomponent pain relief topical medication
US5911980 *27 Jun 199615 Jun 1999Macrochem CorporationLipophilic and amphiphilic or hydrophilic film-forming polymer compositions, and use thereof in topical agent delivery system and method of delivering agents to the skin
US5912271 *21 Jun 199515 Jun 1999Astra AbPharmaceutical preparation for pain management
US5942543 *16 Dic 199624 Ago 1999Ernst; Amy A.Topical anesthetic comprising lidocaine, adrenaline, and tetracaine, and its method of use
US5948416 *8 May 19967 Sep 1999The Procter & Gamble CompanyStable topical compositions
US5958379 *28 Sep 199528 Sep 1999Mika Pharma Gesellschaft Fuer Die Entwicklung Und Vermarktung Pharmazeutischer Producte MbhPharmaceutical composition
US5958446 *4 May 199528 Sep 1999Noven Pharmaceuticals, Inc.Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5990179 *28 Abr 199523 Nov 1999Alza CorporationComposition and method of enhancing electrotransport agent delivery
US5993836 *28 Abr 199830 Nov 1999Castillo; James G.Topical anesthetic formulation
US6004566 *23 Mar 199321 Dic 1999Pharmos Corp.Topical and transdermal delivery system utilizing submicron oil spheres
US6024976 *11 Ago 199715 Feb 2000Noven Pharmaceuticals, Inc.Solubility parameter based drug delivery system and method for altering drug saturation concentration
US6051609 *30 Dic 199818 Abr 2000Tristrata Technology, Inc.Additives enhancing the effect of therapeutic agents
US6193993 *2 Mar 199927 Feb 2001Eisai Co., Ltd.Suppository containing an antidementia medicament
Citada por
Patente citante Fecha de presentación Fecha de publicación Solicitante Título
US7074832 *11 Feb 200311 Jul 2006Bradley Pharmaceuticals, Inc.Compositions containing antimicrobials and urea for the treatment of dermatological disorders and methods for their use
US759245820 Jul 200722 Sep 2009Wright George EDermal anesthetic compounds and pharmaceutical compositions for inducing local anesthesia and mitigating neuropathic pain
US76221308 Feb 200524 Nov 2009Los Angeles Biomedical Research Institute at Harbor UCLA-Medical CenterMethods and compositions for the non-surgical removal of fat
US770058813 Ene 200520 Abr 2010Merkus Franciscus Wilhelmus HePharmaceutical compositions comprising midazolam in a high concentration
US771867427 Sep 200518 May 2010Bridge Pharma, Inc.Methods of relieving neuropathic pain with the S-isomer of 2-{2[N-(2-indanyl)-N-phenylamino]ethyl}piperidine
US775423019 May 200513 Jul 2010The Regents Of The University Of CaliforniaMethods and related compositions for reduction of fat
US81425921 Oct 200927 Mar 2012Mylan Inc.Method for making a multilayer adhesive laminate
US826304729 Sep 200511 Sep 2012Wickenhauser Alan JTopical anesthetic for dental procedures
US829855628 Oct 200930 Oct 2012The Regents Of The University Of CaliforniaMethods and related compositions for the non-surgical removal of fat
US83043831 Feb 20086 Nov 2012Atheronova Operations, Inc.Dissolution of arterial plaque
US8410125 *5 Nov 20082 Abr 2013Yagna LimitedSulfonated precursors of thymidine for the treatment of epithelial hyperplasias
US8501215 *28 Jul 20036 Ago 2013Guohua ChenInjectable multimodal polymer depot compositions and uses thereof
US860967731 Mar 201317 Dic 2013Yagna LimitedMolecules for the photodynamic treatment of tumors and hyperplasias
US862333410 Sep 20127 Ene 2014Alan J. WickenhauserTopical anesthetic
US865305810 Ago 201118 Feb 2014Kythera Biopharmaceuticals, Inc.Compositions comprising deoxycholic acid and salts thereof suitable for use in treating fat deposits
US86976332 Oct 201215 Abr 2014Atheronova Operations, Inc.Dissolution of arterial plaque
US875939116 Ene 200824 Jun 2014Juventio, LlcTopical anesthetic for rapid local anesthesia
US8784892 *7 Jul 201022 Jul 2014Yissum Research Development Company Of The Hebrew University Of JerusalemMethod and composition for burned skin
US884606613 Jun 201330 Sep 2014The Regents Of The University Of CaliforniaMethods and related compositions for reduction of fat and skin tightening
US89208437 Nov 200830 Dic 2014Svip5 LlcSlow release of organic salts of local anesthetics for pain relief
US89687106 Ene 20143 Mar 2015Alan J. WickenhauserTopical anesthetic
US905029316 Jul 20099 Jun 2015Juventio, LlcSmall molecule solubilization system
US91863643 Ene 201317 Nov 2015Kythera Biopharmaceuticals, Inc.Formulations of deoxycholic acid and salts thereof
US928317716 Jul 200815 Mar 2016Juventio, LlcTopical anesthetic for rapid local anesthesia and method of applying a topical anesthetic
US930826224 May 201212 Abr 2016Novaliq GmbhPharmaceutical composition for administration to nails
US9370500 *21 Feb 201221 Jun 2016Centrexion Therapeutics CorporationHigh concentration local anesthetic formulations
US953304825 May 20123 Ene 2017Arisgen SaMucosal delivery of drugs
US9555167 *11 Dic 200631 Ene 20173M Innovative Properties CompanyBiocompatible antimicrobial compositions
US956625120 Dic 201214 Feb 2017Board Of Regents, The University Of Texas SystemVolatile anesthetic compositions and methods of use
US97243567 Feb 20148 Ago 2017Kythera Biopharmaceuticals, Inc.Formulations of deoxycholic acid and salts thereof
US973149018 Nov 201115 Ago 2017Mylan Inc.Method for making a multilayer adhesive laminate
US973754926 Nov 201322 Ago 2017Kythera Biopharmaceuticals, Inc.Formulations of deoxycholic acid and salts thereof
US975745918 Oct 201112 Sep 2017Novaliq GmbhLiquid pharmaceutical composition for the delivery of active ingredients
US975746022 Ene 201312 Sep 2017Novaliq GmbhStabilised protein compositions based on semifluorinated alkanes
US977050812 Sep 201326 Sep 2017Novaliq GmbhSemifluorinated alkane compositions
US20030082225 *19 Oct 20011 May 2003Mason Paul ArthurSterile, breathable patch for treating wound pain
US20030165577 *11 Feb 20034 Sep 2003Bradley Pharmaceuticals, Inc.Novel compositions containing antimicrobials and urea for the treatment of dermatological disorders and methods for their use
US20030175328 *6 Mar 200218 Sep 2003Adi SheferPatch for the controlled delivery of cosmetic, dermatological, and pharmaceutical active ingredients into the skin
US20030175333 *28 Feb 200318 Sep 2003Adi SheferInvisible patch for the controlled delivery of cosmetic, dermatological, and pharmaceutical active ingredients onto the skin
US20040022859 *28 Jul 20035 Feb 2004Guohua ChenInjectable multimodal polymer depot compositions and uses thereof
US20040175333 *17 Mar 20049 Sep 2004Santarpia R. PeterLiquid tooth whitening composition
US20050106214 *10 Nov 200419 May 2005Guohua ChenExcipients in drug delivery vehicles
US20050261258 *8 Feb 200524 Nov 2005Kolodney Michael SMethods and compositions for the non-surgical removal of fat
US20050267080 *19 May 20051 Dic 2005Kolodney Michael SMethods and related compositions for reduction of fat
US20060079559 *27 Sep 200513 Abr 2006Bridge Pharma, Inc.S-isomer of 2-{2[N-(2-indanyl)-N-phenylamino]ethyl}piperidine and other dermal anesthetics
US20060127468 *23 Nov 200515 Jun 2006Kolodney Michael SMethods and related compositions for reduction of fat and skin tightening
US20060147341 *30 Dic 20046 Jul 2006Jahngen Edwin GArticle and method for detecting skin irritants
US20060154906 *13 Mar 200613 Jul 2006Los Angeles Biomedical Research Institute At Harbor-Ucla Medical CenterMethods and related compositions for the non-surgical removal of fat
US20060182705 *11 Feb 200517 Ago 2006Cruse Maria KComposition for reduction and prevention of wrinkles on the skin
US20060182737 *27 Oct 200517 Ago 2006Cruse Maria KWet wipes including a composition for reduction and prevention of wrinkles on the skin
US20060215304 *22 May 200628 Sep 2006Sony CorporationRecording apparatus, server apparatus, recording method, program, and storage medium
US20070071802 *29 Sep 200529 Mar 2007Wickenhauser Alan JTopical anesthetic for dental procedures
US20070224272 *3 Mar 200527 Sep 2007Elka TouitouMethod and composition for burned skin
US20070248587 *22 Feb 200725 Oct 2007Cruse Maria KWet wipes including a composition for reduction and prevention of wrinkles on the skin
US20080033052 *20 Jul 20077 Feb 2008Wright George EDermal anesthetic compounds
US20080142023 *11 Dic 200619 Jun 20083M Innovative Properties CompanyBiocompatible antimicrobial compositions
US20080176948 *16 Ene 200824 Jul 2008Dermworx, Inc.Topical Anesthetic for Rapid Local Anesthesia and Method of Applying a Topical Anesthetic
US20080187569 *1 Feb 20087 Ago 2008Z & Z Medical Holdings, Inc.Dissolution of arterial plaque
US20080200890 *7 Abr 200821 Ago 20083M Innovative Properties CompanyAntimicrobial disposable absorbent articles
US20080227764 *3 Mar 200818 Sep 2008Colin Stanley GoodchildUse of pregnane-diones or diols as neuropathic analgesic agents
US20080249074 *3 Nov 20069 Oct 2008Laboratorios Belmac, S.A.Composition for the Transdermal Administration of Physiologically Active Agents
US20090035348 *16 Sep 20085 Feb 2009Z & Z Medical Holdings, Inc.Dissolution of arterial plaque
US20090048347 *16 Jul 200819 Feb 2009Dermworx IncorporatedTopical anesthetic for rapid local anesthesia and method of applying a topical anesthetic
US20090130048 *19 Nov 200721 May 2009Oronsky Bryan ToddTopical Composition for Treating Pain
US20100016442 *16 Jul 200921 Ene 2010Dermworx IncorporatedSmall molecule solubilization system
US20100034768 *7 Ago 200811 Feb 2010Castillo Miguel AComposition and method for treatment of insect bites
US20100048527 *28 Oct 200925 Feb 2010Kolodney Michael SMethods and compositions for the non-surgical removal of fat
US20100084084 *1 Oct 20098 Abr 2010Miller Ii Kenneth JMethod for Making a Multilayer Adhesive Laminate
US20100179114 *4 Mar 201015 Jul 2010Bridge Pharma, Inc.S-Isomer of 2- piperidine and Other Dermal Anesthetic Agents
US20100233271 *7 Nov 200816 Sep 2010Sawan Samuel PSlow release of organic salts of local anesthetics for pain relief
US20110002896 *18 May 20106 Ene 2011Regents Of The University Of Califorinia, The Los Angeles BiomedicalMethods and related compositions for reduction of fat
US20110052738 *16 Ene 20093 Mar 2011Gary Dean BennettTopical pain formulation
US20110053965 *5 Nov 20083 Mar 2011Asklepius LimitedSulfonated precursors of thymidine for the treatment of epithelial hyperplasias
US20110111010 *7 Jul 201012 May 2011Yissum, Research Development Company Of The Hebrew University Of Jerusalem Ltd.Method and Composition for Burned Skin
US20110159078 *22 Ene 200930 Jun 2011Vapogenix, IncVolatile Anesthetic Compositions and Methods of Use
US20110311611 *22 Jun 201022 Dic 2011Charlene Cheuk Ling NgWater dissolvable adherent article for topical application
US20120149779 *21 Feb 201214 Jun 2012Arcion Therapeutics, Inc.High concentration local anesthetic formulations
US20140004197 *3 Ene 20122 Ene 2014Bastian TheisingerO/w-emulsions comprising semifluorinated alkanes
US20150018387 *11 Sep 201415 Ene 2015Centrexion I, Inc.High concentration local anesthetic formulations
USRE463977 Nov 20089 May 2017Svip5 LlcSlow release of organic salts of local anesthetics for pain relief
EP2526971A1 *25 May 201128 Nov 2012ArisGen SAMucosal delivery of drugs
WO2008087034A2 *17 Ene 200824 Jul 2008Devirex AgCyclodextrin formulations
WO2008087034A3 *17 Ene 200829 Ene 2009Devirex AgCyclodextrin formulations
WO2008089242A1 *16 Ene 200824 Jul 2008Dermworx, IncorporatedTopical anesthetic for rapid local anesthesia and method of applying a topical anesthetic
WO2009094460A3 *22 Ene 200930 Dic 2009Vapogenix, Inc.Volatile anesthetic compositions and methods of use
WO2012160203A1 *25 May 201229 Nov 2012Arisgen SaMucosal delivery of drugs
WO2014110035A1 *7 Ene 201417 Jul 2014Chattem, Inc.Odor suppression of volatile organic analgesic compounds and method of use
Clasificaciones
Clasificación de EE.UU.514/270, 514/304, 514/758, 514/536
Clasificación internacionalA61K31/165, A61K9/70, A61K47/36, A61K47/10, A61K31/245, A61K47/40, A61K47/00, A61K47/14, A61K47/32, A61K9/00
Clasificación cooperativaA61K47/14, A61K47/40, A61K47/36, A61K47/32, A61K9/7015, A61K31/165, A61K31/245, A61K9/0014, A61K47/10
Clasificación europeaA61K9/70D, A61K31/165, A61K31/245, A61K9/00M3
Eventos legales
FechaCódigoEventoDescripción
3 Oct 2002ASAssignment
Owner name: CORIUM INTERNATIONAL, CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CLEARY, GARY W.;MUDUMBA, SRI;CLEARY, COLIN J.;AND OTHERS;REEL/FRAME:013149/0619
Effective date: 20020916
6 Jul 2004ASAssignment
Owner name: CORIUM INTERNATIONAL, CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PARANDOOSH, SHOREH;REEL/FRAME:014819/0209
Effective date: 20040629
5 May 2009ASAssignment
Owner name: SILICON VALLEY BANK, CALIFORNIA
Free format text: SECURITY AGREEMENT;ASSIGNOR:CORIUM INTERNATIONAL, INC.;REEL/FRAME:022634/0119
Effective date: 20090430
20 Dic 2011ASAssignment
Owner name: OXFORD FINANCE LLC, AS COLLATERAL AGENT, VIRGINIA
Free format text: SECURITY AGREEMENT;ASSIGNOR:CORIUM INTERNATIONAL, INC.;REEL/FRAME:027422/0717
Effective date: 20111107
30 Ago 2012ASAssignment
Owner name: CORIUM INTERNATIONAL, INC., CALIFORNIA
Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:OXFORD FINANCE LLC;REEL/FRAME:028884/0179
Effective date: 20120816